Prostate cancer is the most common malignancy in American men and the second leading cause of cancer-related death. Despite significant advances we continue to need improvement in therapeutic modalities to prevent progression from early stage to advanced metastatic disease and to further improve survival in patients with castration-resistant prostate cancer (CRPC). It has now been clearly demonstrated that the immune system is one of the most important targets in the treatment of cancer. Although there have been spectacular success stories in individual patients there is now a growing consensus that to truly impact patient care, immunotherapy will likely need to be combined with other agents. Over the past 20 years, based on preclinical studies from Dr. Jeffrey Schlom (Laboratory of Tumor Immunology and Biology, LTIB), I have led a series of trials in which vaccine therapy has been combined with hormonal therapy, radiotherapy, chemotherapy, small molecules, and other immunotherapy agents. The immune responses and clinical activity have been used by others as the scientific rationale to combine vaccines with other agents in large trials. In combination with Dr. William Figg (GMB), we are exploring non-immune targeted therapies in men with CRPC with an increased focus on improving patient selection. As we move into the world of precision medicine I have been very fortunate to have developed a strong working relationship with Dr. Peter Choyke (Molecular Imaging Program). Increasingly, we are discovering that imaging can not only significantly increase the detection of cancer but has the potential to improve our understanding of cancer biology. I am fortunate to be able to work in a very collaborative environment in the Center for Cancer Research (CCR) of the NCI. In addition to those mentioned above, I chair a group of 15 Senior NCI Investigators from the full breadth of prostate cancer investigation. These monthly working meetings have been incredibly valuable in integrating laboratory and clinical studies in prostate cancer Accomplishments 1. Completed multiple clinical studies in patients with different stages of prostate cancer, demonstrating that a vaccine strategy using recombinant vaccinia (rV)-prostate-specific antigen (PSA) + rV-B7.1 followed by recombinant fowlpox (rF)-PSA could be safely employed with external beam radiotherapy (EBRT), second-line hormone therapy, checkpoint inhibitors and chemotherapy. 2. Demonstrated long-term PSA-specific immune responses when vaccine was combined with EBRT as compared to EBRT alone. 3. Completed the first clinical trial to show the activity of ipilimumab in combination with a poxviral vaccine. 4. Demonstrated in a randomized trial that patients who commenced with vaccine and then added nilutamide had a superior median survival compared to patients who had nilutamide first and vaccine added (6.4 vs. 4.0 years; P = 0.052). 5. Demonstrated a much longer than predicted survival in patients with metastatic CRPC treated with rV-/rF-PSA-TRICOM. This correlated strongly with the development of potent immune responses . 6. Established the first working group convened to establish parameters for the use of PSA doubling time (PSADT) in prostate cancer, standardized the calculation of PSADT, and defined criteria for the use of PSADT in clinical practice . 7. Demonstrated the safety and immunologic activity of an intraprostatic vaccine. 8. Demonstrated that the relationship between growth rate kinetics and time to death is independent of the mechanism of the anticancer therapy, with the exception of immunotherapy . 9. Published the largest series of patients evaluating the timing of testosterone and DHT increase after cessation of GnRH-A therapy, and showed that after 6 months of GnRH-A therapy, DHT and testosterone levels did not return to normal for a median of 14.9 and 16.6 weeks, respectively. 10. Demonstrated that the polymorphism in a transporter that increases testosterone import, SLC01B3, is associated with a shorter time to androgen independence in prostate cancer patients treated with androgen-deprivation therapy (ADT). 11. Demonstrated radiographic improvement in patients on the sorafenib and cediranib trials despite increasing serum PSA levels. 12. Demonstrated objective tumor responses in docetaxel-resistant prostate cancer patients treated with cediranib. 13. Completed the largest phase III trial testing an antiangiogenic agent in the setting of intermittent hormonal therapy for patients with biochemical recurrence after surgery or radiotherapy for patients with localized prostate cancer. 14. Demonstrated that thalidomide could increase the length of time off of hormonal therapy in patients treated with intermittent hormonal therapy. 15. Completed the first phase I study of lenalidomide in solid tumors. 16. Showed that the combination of thalidomide and bevacizumab with docetaxel is associated with high response rates (90% in PSA and 63% in measurable disease), leading to one of the longest progression-free survival (PFS) (18.2 months) and median survival (26.7 months) of any regimen in this clinical setting. 17. Demonstrated significant activity combining a hormonal agent with docetaxel in CRPC. 18. Established kinetics of 18F-sodium fluoride for oncology using current PET camera. 19. Demonstrated the safety and impact on angiogenic markers of an anti-CD105 antibody. 20. Demonstrated the safety and clinical activity of ferumoytol for MR lymphography. 21. Opened the first trial using MRI to screen men at high genetic risk for Prostate Cancer